Biaryl PDE4 inhibitors for treating inflammatory, cardiovascular and CNS disorders

1. A compound of formula

or salt thereof wherein

R 1a is phenyl;

R 14 is chosen from —CH 2 NHC(═O)NH 2 , —NHC(═O)NH 2 , —NHC(═O)NHEt, —CH 3 , —CH 2 CF 3 , —CH 2 NHC(═O)CH 3 , —NHCH 3 , —NHEt, —NH(tBoc), —CHO, —NHC(═O)NHCH 2 CH 2 C1, —NHSO 2 NH 2 , —N(CH 3 ) 2 , —NH 2 , —COOH, —C(═O)NH 2 , —CH 2 C(═O)NH 2 , —CH 2 COOH, —CH 2 COOEt, —CN, —OCH 3 , —OC(═O)NH 2 , —NH(CH 3 )C(═O)NH 2 , halogen, —CH 2 NHC(═O)OEt, —NHSO 2 CH 3 , —N(SO 2 CH 3 ) 2 , —NHC(═O)OCH 3 , —OH, —CH 2 NHC(═O)N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —SO 2 NH 2 , —NHC(═O)NHCH 2 COOH, —CH 2 NHCHO, —NHC(═O)NHCH 2 COOEt, —COOCH 3 , —COOEt, —NHC(═O)NH(CH 2 ) 3 COOEt, —NHC(═O)NH(CH 2 ) 2 COOEt, —NH(Et)C(═O)OEt, —NHC(═O)NH(CH 2 ) 2 COOH, —CH 2 NHSO 2 CH 3 , —OEt, —NHC(═O)CH 2 N(CH 3 ) 2 , —NHC(═O)NH(CH 2 ) 3 COOH, —NHC(═O)CH 2 NH 2 , —NHC(═O)CH 2 CH 2 NH 2 , —NHC(═O)CH 2 NH(tBoc), —OCH 2 CH 2 N(CH 3 ) 2 , —OCH 2 CH 2 OCH 3 , 3′-nitro-6-methoxybiphenyl-3-ylmethyl, tetrahydroimidazol-2-on-1-yl, 3-methyltetrahydroimidazol-2-one-1-yl, pyrazol-1-yl,

and residues of amino acids, amino acid amides, protected residues of amino acids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides, wherein said amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, selenocysteine, serine, threonine, tryptophan, tyrosine, and valine;

R 15 is chosen from H, NO 2 , OH, NH 2 , and —NHSO 2 NH 2 ; or

R 15 together with R 14 forms methylene dioxy;

R 3 is chosen from —C(═O)NH 2 , —(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-R 30 , —(C 2 -C 6 )alkyl-R 31 , and saturated 4- or 5-membered heterocycle optionally substituted with methyl;

R 30 is chosen from —C(═O)NH 2 and 4- or 5-membered heterocycle optionally substituted with methyl;

R 31 is chosen from (C 1 -C 4 )alkoxy, amino, hydroxy, (C 1 -C 6 )alkylamino and di(C 1 -C 6 )alkylamino;

R 4 is chosen from H and F;

R 6 is chosen from H, (C 1 -C 6 )alkyl and halogen;

X is N, N→O, or C—R 5 ;

R 5 is chosen from H, halogen, OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, CF 3 , CN, NH 2 , CH 2 OH, CH 2 NH 2 and C≡CH;

M is chosen from —C(R 20 )(R 21 )—, —O—, —NR 22 —, —S(O) n —, —C(═O)—, —C(R 20 )(R 21 )C(R 20 )(R 21 )—, —C(R 20 )═C(R 21 )—, —C(R 20 )(R 21 )—O—, —C(R 20 )(R 21 )—NR 22 —, —C(R 20 )(R 21 )—S(O) n —, —C(R 20 )(R 21 )—C(=O)—, —O—C(R 20 )(R 21 )—, —NR 22 —C(R 20 )(R 21 )—, —S(O) n —C(R 20 )(R 21 )—, —C(═O)—C(R 20 )(R 21 )— and

is a five or six-membered ring optionally substituted with methyl;

n is zero, one or two; and

R 20 , R 21 and R 22 are selected independently in each occurrence from H and (C 1 -C 4 )alkyl;

R 7 is chosen from hydrogen, halogen, nitro, cyano, halo(C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )oxaalkyl, carboxy, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl (—CONH 2 ), (C 1 -C 6 )alkylaminocarbonyl, acyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino, di[(C 1 -C 6 )alkyl]amino, mercapto, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylsulfonamido, acylamino, amidino, phenyl, benzyl, monocyclic heterocyclyl, phenoxy, benzyloxy, and monocyclic heteroaryloxy; and

R 8 and R 13 are chosen independently from H and F,

wherein all of R 7 , R 8 , and R 13 may not be hydrogen.

2. A compound or salt according to claim 1 wherein X is N or N→O.

3. A compound or salt according to claim 1 wherein X is CR 5 .

4. A compound or salt according to claim 1 wherein M is chosen from —CH 2 —, —CH(OH)—, —C[(CH 3 )(OH)]—, —C[(CH 3 )(NH 2 )]—, —C(═O)—, —O—, —NH—, —N(CH 3 )—, —S(O) n —, —CH 2 NH—, —CH 2 CH 2 —, —CH═CH—, —CH 2 S(O) n —, —CH 2 O— and

5. A compound or salt according to claim 1 , wherein R 8 and R 13 are H and R 7 is chosen from fluoro, chloro, bromo, nitro, cyano, acetyl, trifluoromethyl, methoxy, trifluoromethoxy, oxadiazolyl, tetrazolyl, methylthio, methanesulfinyl, methanesulfonyl, methansulfonamido, methoxymethyl, hydroxyethyl, and morpholinyl.

6. A compound or salt according to claim 1 wherein R 7 is chosen from halogen, nitro, acetyl, hydroxyethyl, amino, methylthio, trifluoromethyl, methoxymethyl, methoxycarbonyl, trifluoromethoxy, cyano and 1,3,4-thiadiazol-2-yl.

7. A compound or salt according to claim 1 wherein R 5 is fluoro, H, CN or OH.

8. A compound or salt according to claim 1 wherein R 3 is methyl or fluoromethyl.

9. A compound or salt of formula:

wherein

R 3 is methyl or fluorinated methyl;

Y is CH;

X is N, N→O, or C—R 5 ;

R 5 is chosen from H, halogen, OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, CF 3 , CN, NH 2 CH 2 OH, CH 2 NH 2 and C≡CH;

M is chosen from —C(R 20 )(R 21 )—, —O—, —NR 22 —, —S(O) n —, —C(═O)—, —C(R 20 )(R 21 )C(R 20 )(R 21 ), —C(R 20 )═C(R 21 )—, —C(R 20 )(R 21 )—O—, —C(R 20 )(R 21 )—NR 22 —, —C(R 20 )(R 21 )—S(O) n —, —C(R 20 )(R 21 )—C(═O)—, —O—C(R 20 )(R 21 )—, —NR 22 —C(R 20 )(R 21 )—, —S(O) n , —C(R 20 )(R 21 )—, —C(═O)—C(R 20 )(R 21 )— and

is a five or six-membered ring optionally substituted with methyl;

n is zero, one or two and

R 20 , R 21 and R 22 are selected independently in each occurrence from H and (C 1 -C 4 )alkyl;

R 27a is chosen from halogen, cyano, acetyl, methylthio, nitro and trifluoromethyl; and

R 16 is chosen from —NR 17 C(═O)NR 18 R 19 , halogen, acetamide, carbamate, and

wherein

is a 4-7 membered ring heterocycle attached through its nitrogen;

R 17 , and R 18 are independently chosen from H, (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl;

R 19 is chosen from H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, —[(C 1 -C 6 )alkyl]COOH, and —[(C 1 -C 6 )alkyl]COO(C 1 -C 6 )alkyl; and

R 20 is chosen from a carboxylic acid, a carboxamide, a carboxylic ester, a primary, secondary or tertiary alcohol and a primary, secondary or tertiary amine.

10. A compound or salt according to claim 9 wherein

X is CH, CF or N—O;

M is —CH 2 — or —S—;

R 27a is chosen from chloro, cyano, acetyl and methylthio; and

R 16 is chosen from —NR 17 C(═O)NR 18 R 19 , halogen, —NHCOCH 3 , —NHCOOC(CH 3 ) 3 ,

11. A compound or salt according to claim 10 wherein Y is CH; M is —CH 2 —; R 27a is chloro; and R 16 is —NR 17 C(═O)NR 18 R 19 .

12. A compound or salt according to claim 11 wherein R 16 is —NR 17 C(═O)NR 18 R 19 and R 17 , R 18 and R 19 are all hydrogen.

13. A salt of a compound of claim 1 wherein the salt is a pharmaceutically acceptable salt.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt according to claim 1 .

15. A pharmaceutical composition comprising

(a) a pharmaceutically acceptable carrier;

(b) a compound or pharmaceutically acceptable salt according to claim 1 ; and

(c) a second agent chosen from cholinesterase inhibitors, NMDA antagonists, calpain inhibitors and antioxidants.

16. A pharmaceutical composition according to claim 15 wherein said second agent is chosen from tacrine, huperzine, donepezil, lanicemine, remacemide, neramexane, memantine, vitamin E and coenzyme Q10.

17. A compound or salt according to claim 1 wherein R 3 is chosen from —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2 and —CH 2 F.

18. A compound or salt according to claim 1 wherein R 5 is chosen from H, —F, —OH, —CH 3 , —OCH 3 , —CF 3 , —CN, —NH 2 and —CCH.

19. A compound or salt according to claim 1 wherein R 7 is chosen from halogen, nitro, acetyl, hydroxyethyl, —SCH 3 , methoxycarbonyl, —SOCH 3 , —SO 2 CH 3 , —OCH 3 , —OCF 3 , —CN, —CF 3 , and —CH 2 OCH 3 .

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt according to claim 9 .

21. A pharmaceutical composition comprising

(a) a pharmaceutically acceptable carrier;

(b) a compound or pharmaceutically acceptable salt according to claim 9 ; and

(c) a second agent chosen from cholinesterase inhibitors, NMDA antagonists, calpain inhibitors and antioxidants.

22. A pharmaceutical composition according to claim 21 wherein said second agent is chosen from tacrine, huperzine, donepezil, lanicemine, remacemide, neramexane, memantine, vitamin E and coenzyme Q10.